Celexii 100 mg and 200 mg Hard gelatine capsules

• Symptomatic treatment of inflammation and pain in osteoarthritis and rheumatoid arthritis.
• Treatment of pain after dental surgery.
• Treatment of mild to moderate post-operative pain.
• Treatment of mild to moderate musculoskeletal pain.
• Treatment of mild to moderate primary dysmenorrhoea.
• Relief of symptoms of ankylosing spondylitis.

Posology: As the cardiovascular risks of CELEXII may increase with dose and duration of exposure, the lowest effective daily dose should be used, for the shortest possible duration of treatment.

Osteoarthritis: The recommended daily dose is 200 mg, taken as a single dose or as two divided doses. Doses up to 400 mg per day have been studied.

Rheumatoid arthritis: The recommended daily dose is 100 mg or 200 mg twice per day.

Pain post dental surgery: The recommended dose is 100 mg to 200 mg, up to a maximum daily dose of 400 mg. Dosing intervals should not be less than 4 hours.

Mild to moderate post-operative pain: The recommended dose is 200 mg once daily. Some patients may benefit from an additional 200 mg dose.

Mild to moderate musculoskeletal pain: The recommended dose is 200 mg twice daily.

Mild to moderate primary dysmenorrhoea: The recommended dose is 400 mg initially, followed by an additional 200 mg dose if needed on the first day. On subsequent days, the recommended dose is 200 mg twice daily.

Ankylosing spondylitis: The recommended daily dose is 200 mg, administered as a single dose or as 100 mg twice daily. Some patients may benefit from a total daily dose of 400 mg.

Special populations

Hepatic impairment: No dosage adjustment is necessary in patients with mild hepatic impairment. Introduce CELEXII at the lowest recommended dose in patients with moderate hepatic impairment. There is no clinical experience in patients with severe hepatic impairment (see sections 4.3 and 5.2).

Renal impairment: No dosage adjustment is necessary in patients with mild or moderate renal impairment. There is no clinical experience in patients with severe renal impairment (see sections 4.3 and 5.2).

Elderly: No dosage adjustment is necessary. However, for elderly patients with a body mass of 50 kg or less, it is advisable to initiate therapy at the lowest recommended dose.

Children: As no data are available, CELEXII is not recommended in persons under 18 years old.

Method of administration: Oral use. CELEXII should be taken whole with a glass of water, with or without food.

• Hypersensitivity to celecoxib, or any other excipient of CELEXII (see section 6.1).
• Known hypersensitivity to sulphonamide.
• Severe hepatic impairment (serum albumin < 25 g/L or Child-Pugh score u2265 10).
• Severe renal impairment with estimated creatinine clearance < 30 mL/min.
• Asthma, urticaria or allergic-type reactions precipitated by aspirin or non-steroidal anti-inflammatory drugs (NSAIDs), including other cyclooxygenase 2 (COX-2) specific inhibitors.
• Established ischaemic heart disease and/or cerebrovascular disease (stroke) and peripheral arterial disease.
• Peri-operative analgesia against the background of coronary artery bypass surgery (CABG).
• Active peptic ulceration or gastrointestinal (GI) bleeding.
• Inflammatory bowel disease.
• In pregnancy and in women of childbearing potential unless using an effective method of contraception (see section 4.6). The potential for human risk in pregnancy is unknown but cannot be excluded.
• Breastfeeding (see section 4.6).

CELEXII may predispose to cardiovascular incidents, cerebrovascular incidents, gastrointestinal events or cutaneous reactions that may be fatal. Safety and efficacy of CELEXII have not been established for treatment exceeding 12 weeks in osteoarthritis and 24 weeks in rheumatoid arthritis.

Cardiovascular effects: Increased number of serious cardiovascular (CV) events, mainly myocardial infarction, has been reported in patients with sporadic adenomatous polyps treated with celecoxib (as in CELEXII) at doses of 200 mg twice daily and 400 mg twice daily, compared to placebo (see section 5.1). As the cardiovascular risks of CELEXII may increase with dose and duration of exposure, the shortest duration possible and the lowest effective daily dose should be used. NSAIDs, including COX-2 selective inhibitors, have been associated with increased risk of cardiovascular and thrombotic adverse events when taken long term. The exact magnitude of the risk associated with a single dose has not been determined, nor has the exact duration of therapy associated with increased risk. The patient's need for symptomatic relief and response to therapy should be re-evaluated periodically, especially in patients with osteoarthritis (see sections 4.2, 4.3, 4.8 and 5.1). Caution is advised when CELEXII is prescribed to patients with risk factors for cardiovascular events (e.g. hypertension, hyperlipidaemia, diabetes mellitus, smoking).

CELEXII is not a substitute for aspirin for prophylaxis of cardiovascular thromboembolic diseases because of their lack of antiplatelet effects. Therefore, antiplatelet therapies should not be discontinued.

Anaphylactoid reactions: As with NSAIDs in general, anaphylactoid reactions have occurred in patients exposed to CELEXII (see section 4.3).

Gastrointestinal (GI) effects: Upper and lower gastrointestinal complications (perforations, ulcers or bleedings (PUBs)), some resulting in fatalities, have occurred in patients treated with celecoxib (as in CELEXII). Caution is advised with treatment of patients most at risk of developing a gastrointestinal complication with NSAIDs; the elderly, patients using any other NSAID or antiplatelet medicines (such as aspirin) or glucocorticoids concomitantly, patients using alcohol, or patients with a prior history of gastrointestinal disease, such as ulceration and GI bleeding. When CELEXII is taken concomitantly with aspirin (even at low doses), there is further increase in the risk of gastrointestinal adverse effects for celecoxib (gastrointestinal ulceration or other gastrointestinal complications). A significant difference in GI safety between selective COX-2 inhibitors plus aspirin vs NSAIDs plus aspirin has not been demonstrated in long-term clinical trials.

Concomitant NSAID use: The concomitant use of CELEXII and a non-aspirin NSAID should be avoided.

Fluid retention and oedema: Fluid retention and oedema have been observed in patients taking celecoxib (as in CELEXII). Therefore, CELEXII should be used with caution in patients with history of cardiac failure, left ventricular dysfunction or hypertension, and in patients with pre-existing oedema from any other reason, since prostaglandin inhibition may result in deterioration of renal function and fluid retention. Caution is also required in patients taking diuretic treatment or otherwise at risk of hypovolaemia. Patients with pre-existing congestive heart failure or hypertension should be closely monitored.

Hypertension: NSAIDs, including celecoxib (as in CELEXII) can lead to the onset of new hypertension or worsening of pre-existing hypertension, either of which may contribute to the increased incidence of cardiovascular events. Therefore, blood pressure should be monitored closely during the initiation of therapy with CELEXII and throughout the course of therapy.

Hepatic and renal effects: Compromised renal or hepatic function and especially cardiac dysfunction are more likely in the elderly and therefore medically appropriate supervision should be maintained. NSAIDs, including CELEXII, may cause renal toxicity. Celecoxib has shown renal effects similar to those observed with comparator NSAIDs. Patients at greatest risk for renal toxicity are those with impaired renal function, heart failure, liver dysfunction, those taking diuretics, angiotensin converting enzyme (ACE)-inhibitors, angiotensin II receptor antagonists, and the elderly (see section 4.5). Such patients should be carefully monitored while receiving treatment with CELEXII. Severe hypokalaemia and renal tubular acidosis (RTA) have been reported with the prolonged use of other NSAIDs (such as ibuprofen) at higher than recommended doses. Caution is advised with the use of CELEXII. Some cases of severe hepatic reactions, including fulminant hepatitis (some with fatal outcome), liver necrosis and hepatic failure (some with fatal outcome or requiring liver transplant), have been reported with celecoxib (contained in CELEXII). Among the cases that reported time to onset, most of the severe adverse hepatic events developed within one month after initiation of celecoxib (contained in CELEXII) treatment (see section 4.8). If during treatment, patients deteriorate in any of the organ system functions described above, appropriate measures should be taken and discontinuation of CELEXII therapy should be considered. Caution should be used when initiating treatment in patients with dehydration. It is advisable to first rehydrate patients and then commence with CELEXII therapy.

CYP2D6 inhibition: Celecoxib inhibits CYP2D6. Although it is not a strong inhibitor of this enzyme, a dose reduction of CELEXII may be necessary for individually dose-titrated medicines that are metabolised by CYP2D6 (see section 4.5).

CYP2C9 poor metabolisers: Patients known to be CYP2C9 poor metabolisers should be treated with caution.

Skin and systemic hypersensitivity reactions: Serious skin reactions, some of them fatal, including exfoliative dermatitis, Stevens-Johnson syndrome, and toxic epidermal necrolysis, have been reported in association with the use of celecoxib (as in CELEXII), see section 4.8. Patients appear to be at highest risk for these events early in the course of therapy; the onset of the event occurring in the majority of cases within the first month of treatment. Serious hypersensitivity reactions (including anaphylaxis, angioedema and drug reaction with eosinophilia and systemic symptoms (DRESS), or hypersensitivity syndrome), have been reported in patients receiving celecoxib (as in CELEXII), see section 4.8. Patients with a history of sulphonamide allergy or any medicine allergy may be at greater risk of serious skin reactions or hypersensitivity reactions (see section 4.3). CELEXII should be discontinued at the first appearance of skin rash, mucosal lesions, or any other sign of hypersensitivity.

Risk of drug reaction with eosinophilia and systemic symptoms (DRESS): Drug reaction with Eosinophilia and Systemic Symptoms (DRESS) has been reported in patients taking NSAIDs such as CELEXII. Some of these events have been fatal or life-threatening. DRESS typically, although not exclusively, presents with fever, rash, lymphadenopathy, and/or facial swelling. Other clinical manifestations may include hepatitis, nephritis, haematological abnormalities, myocarditis, or myositis. Sometimes symptoms of DRESS may resemble an acute viral infection. Eosinophilia is often present. Because this disorder is variable in its presentation, other organ systems not noted here may be involved. It is important to note that early manifestations of hypersensitivity, such as fever or lymphadenopathy, may be present even though rash is not evident. If such signs or symptoms are present, discontinue CELEXII and evaluate the patient immediately.

General: CELEXII may mask fever and other signs of inflammation.

Use with oral anticoagulants: In patients on concurrent therapy with warfarin, serious bleeding events, of which some were fatal, have been reported (see sections 4.8 and 4.5). Because increases in prothrombin time (INR) have been reported, anticoagulant activity should be closely monitored in patients receiving warfarin/coumarin-type oral anticoagulants, particularly when therapy with CELEXII is initiated, or its dose is changed (see section 4.5). Concomitant use of anticoagulants with NSAIDS may increase the risk of bleeding. Caution should be exercised when combining CELEXII with warfarin or other oral anticoagulants, including novel anticoagulants (e.g., apixaban, dabigatran, and rivaroxaban).

Excipient warnings: CELEXII 100 mg and 200 mg contains lactose monohydrate (see sections 2 and 6.1). Patients with rare hereditary problems of galactose intolerance, total lactase deficiency or glucose/galactose malabsorption should not take CELEXII.

Pharmacodynamic interactions

Anticoagulants: In patients on concurrent therapy with warfarin, increases in prothrombin time (INR) have been reported (see section 4.4). Anticoagulant activity should be monitored particularly in the first few days after initiating or changing the dose of CELEXII in patients receiving warfarin or other anticoagulants since these patients have an increased risk of bleeding complications. Therefore, patients receiving oral anticoagulants should be closely monitored for their prothrombin time INR, particularly in the first few days when therapy with CELEXII is initiated or its dose is changed (see section 4.4). Bleeding events in association with increases in prothrombin time (INR) have been reported, predominantly in the elderly, in patients receiving celecoxib (as in CELEXII) concurrently with warfarin, some of them fatal.

Anti-hypertensives: NSAIDs, including CELEXII, may reduce the effect of antihypertensive medicines (including ACE inhibitors, angiotensin II receptor antagonists, diuretics and beta-blockers). This interaction should be given consideration in patients taking CELEXII concomitantly with antihypertensive medicines. As for NSAIDs, the risk of acute renal insufficiency, which is usually reversible, may be increased in some patients with compromised renal function (e.g. dehydrated patients, patients on diuretics or elderly patients) when ACE inhibitors or angiotensin II receptor antagonists, and/or diuretics are combined with NSAIDs, including CELEXII (see section 4.4). Therefore, the combination should be administered with caution, especially in the elderly. Patients should be adequately hydrated and consideration should be given to monitoring of renal function after initiation of concomitant therapy, and periodically thereafter.

Clinical studies, as well as post-marketing observations, have shown that NSAIDs can reduce the natriuretic effect of furosemide and thiazides in some patients. This response has been attributed to inhibition of renal prostaglandin synthesis.

Ciclosporin and tacrolimus: Co-administration of NSAIDs (including CELEXII) and ciclosporin or tacrolimus may increase the nephrotoxic effect of ciclosporin or tacrolimus, respectively. Renal function should be monitored when CELEXII and any of these medicines are combined.

Aspirin: CELEXII can be used with low-dose aspirin. However, concomitant administration of aspirin with CELEXII may result in an increased rate of GI ulceration or other complications, compared to use of CELEXII alone. Because of its lack of platelet effects, CELEXII is not a substitute for aspirin for cardiovascular prophylaxis. There is no consistent evidence that concurrent use of aspirin mitigates the increased risk of serious cardiovascular thrombotic events associated with CELEXII. An increased risk of gastrointestinal ulceration or other gastrointestinal complications compared to use of CELEXII alone was shown for concomitant administration of low-dose aspirin.

Pharmacokinetic interactions

Effects of CELEXII on other medicines

CYP2D6 inhibition: Celecoxib is an inhibitor of CYP2D6. The plasma concentrations of medicines that are substrates of this enzyme may be increased when CELEXII is used concomitantly. Examples of medicines which are metabolised by CYP2D6 are antidepressants (tricyclics and SSRIs), neuroleptics, antidysrhythmic medicines, etc. The dose of individually dose-titrated CYP2D6 substrates may need to be reduced when treatment with CELEXII is initiated or increased if treatment with CELEXII is terminated. Concomitant administration of celecoxib 200 mg twice daily resulted in 2.6-fold and 1.5-fold increases in plasma concentrations of dextromethorphan and metoprolol (CYP2D6 substrates), respectively. These increases are due to celecoxib CYP2D6 inhibition of the CYP2D6 substrate metabolism.

CYP2C19 inhibition: In vitro studies have shown some potential for celecoxib to inhibit CYP2C19 catalysed metabolism. The clinical significance of this in vitro finding is unknown. Examples of medicines which are metabolised by CYP2C19 are diazepam, citalopram and imipramine.

Methotrexate: In patients with rheumatoid arthritis celecoxib had no statistically significant effect on the pharmacokinetics (plasma or renal clearance) of methotrexate (in rheumatologic doses). However, adequate monitoring for methotrexate-related toxicity should be considered when combining these two medicines.

Lithium: In healthy persons, co-administration of celecoxib 200 mg twice daily with 450 mg twice daily of lithium resulted in a mean increase in C max of 16 % and in area under the curve (AUC) of 18 % of lithium. Therefore, patients on lithium treatment should be closely monitored when CELEXII is introduced or withdrawn.

Oral contraceptives: In an interaction study, celecoxib had no clinically relevant effects on the pharmacokinetics of oral contraceptives (1 mg norethisterone/35 micrograms ethinylestradiol).

Glibenclamide/tolbutamide: Celecoxib does not affect the pharmacokinetics of tolbutamide (CYP2C9 substrate), or glibenclamide to a clinically relevant extent.

Phenytoin: In specific studies in healthy volunteers with other medicines metabolised by CYP2C9, celecoxib was found to produce no clinically significant pharmacokinetic interaction with phenytoin.

Effects of other medicines on CELEXII

CYP2C9 poor metabolisers: In individuals who are CYP2C9 poor metabolisers and demonstrate increased systemic exposure to celecoxib, concomitant treatment with CYP2C9 inhibitors such as fluconazole could result in further increases in celecoxib exposure. Such combinations should be avoided in known CYP2C9 poor metabolisers (see section 4.4).

CYP2C9 inhibitors and inducers: Since celecoxib is predominantly metabolised by CYP2C9, CELEXII should be used at half the recommended dose in patients receiving fluconazole. Concomitant use of 200 mg single dose of celecoxib and 200 mg once daily of fluconazole, a potent CYP2C9 inhibitor, resulted in a mean increase in celecoxib C max of 60 % and in AUC of 130 %. Concomitant use of inducers of CYP2C9 such as rifampicin, carbamazepine and barbiturates may reduce plasma concentrations of celecoxib. Ketoconazole and antacids: Ketoconazole or antacids have not been observed to affect the pharmacokinetics of celecoxib.

Paediatric populations: Interaction studies have only been performed in adults.

Pregnancy: CELEXII is contraindicated in pregnancy (see section 4.3). Regular use of non-steroidal inflammatory drugs during pregnancy may result in:

First trimester: Inhibition of prostaglandin synthesis may adversely affect the pregnancy and/or the embryo/foetal development. Data from epidemiological studies raise concern about an increased risk of miscarriage and of cardiac malformation and gastroschisis after use of a prostaglandin synthesis inhibitor in early pregnancy. The absolute risk for cardiovascular malformation was increased from less than 1 %, up to approximately 1.5 %. In animals, administration of a prostaglandin synthesis inhibitor has been shown to result in increased pre- and post-implantation loss and embryo-foetal lethality. In addition, increased incidences of various malformations including cardiovascular, have been reported in animals given a prostaglandin synthesis inhibitor during the organogenetic period.

Second and Third trimester: During the third trimester of pregnancy, prostaglandin synthesis inhibitors, may expose the foetus to: cardiopulmonary toxicity (with premature closure of the ductus arteriosus and pulmonary hypertension); renal dysfunction, which may progress to renal failure with oligo-hydroamniosis. At the end of pregnancy, the mother and the neonate may be exposed to; possible prolongation of bleeding time, an anti-aggregating effect which may occur even at very low doses; inhibition of uterine contractions resulting in delayed or prolonged labour.

Breastfeeding: Limited data indicate that CELEXII is excreted in breast milk and must therefore not be used during lactation.

Fertility: Based on the mechanism of action, the use of NSAIDs, including CELEXII, may delay or prevent rupture of ovarian follicles, which has been associated with reversible infertility in some women.

Patients who experience dizziness, vertigo or somnolence (see section 4.8) while taking CELEXII should refrain from driving or operating machinery.

Tabulated list of adverse reactions:

System Organ Class Frequency Side effects

Infections and infestations Frequent Less frequent Sinusitis, upper respiratory tract infection, pharyngitis, urinary tract infection, bronchitis Helicobacter infection, herpes zoster, erysipelas, bronchopneumonia, labyrinthitis, gingival infection

Blood and the lymphatic system disorders Less frequent Anaemia, leukopenia, thrombocytopenia, pancytopenia, agranulocytosis, ecchymosis

Immune system disorders Frequent Less frequent Frequency unknown Hypersensitivity, allergy aggravated Anaphylactic shock, anaphylactic reaction, angioedema Anaphylaxis

Metabolism and nutrition disorders Frequent Less frequent Increased weight Hyperkalaemia, increased blood sodium Frequency unknown Hypokalaemia

Psychiatric disorders Frequent Less frequent Insomnia Anxiety, depression, fatigue, confusional state, hallucinations

Nervous system disorders Frequent Frequency unknown Dizziness, hypertonia, headache Cerebral infarction (stroke), paraesthesia, somnolence, ataxia, dysgeusia, intracranial haemorrhage (including fatal intracranial haemorrhage), aseptic meningitis, epilepsy (including aggravated epilepsy), ageusia, anosmia

Eye disorders Less frequent Blurred vision, conjunctivitis, eye haemorrhage, retinal artery occlusion, retinal vein occlusion, vitreous floaters, conjunctival haemorrhage

Ear and labyrinth disorders Less frequent Tinnitus, hypoacusis, dysphonia

Cardiac disorders Frequent Less frequent Frequency unknown Myocardial infarction, angina pectoris Cardiac failure, palpitations, tachycardia, dysrhythmia Cardiovascular thrombotic incidents

Vascular disorders Frequent Less frequent Hypertension (including aggravated hypertension) Pulmonary embolism, flushing, vasculitis, deep vein thrombosis

Respiratory, thoracic and mediastinal disorders Frequent Less frequent Rhinitis, cough, dyspnoea Bronchospasm, pneumonitis

Gastrointestinal disorders Frequent Less frequent Nausea, abdominal pain, diarrhoea, dyspepsia, flatulence, vomiting, dysphagia, irritable bowel syndrome, tooth disorder Constipation, gastritis, stomatitis, gastrointestinal inflammation (including aggravation of gastrointestinal inflammation), eructation, gastrointestinal haemorrhage, duodenal ulcer, gastric ulcer, oesophageal ulcer, intestinal ulcer, large intestinal ulcer, intestinal perforation, oesophagitis, melaena, pancreatitis, colitis, haemorrhoidal haemorrhage, frequent bowel movements, mouth ulceration

Hepato-biliary disorders Less frequent Abnormal hepatic function, increased hepatic enzymes (including increased AST and ALT), hepatitis, hepatic failure (sometimes fatal or requiring liver transplant), fulminant hepatitis (some with fatal outcome), hepatic necrosis, cholestasis, cholestatic jaundice

Skin and subcutaneous tissue disorders Frequent Less frequent Rash, pruritus (includes generalised pruritus) Urticaria, ecchymosis, alopecia, photosensitivity, exfoliative dermatitis, erythema multiforme, Stevens-Johnson syndrome, toxic epidermal necrolysis, drug reaction with eosinophilia and systemic symptoms (DRESS), acute generalised exanthematous pustulosis (AGEP), bullous dermatitis, lipoma, allergic dermatitis, ganglion

Musculoskeletal, and connective tissue disorders Frequent Arthralgia Less frequent Muscle spasms (leg cramps), myositis, lower limb fracture

Renal and urinary disorders Less frequent Frequency unknown Increased blood creatinine, increased blood urea, acute renal failure, hyponatraemia, tubulointerstitial nephritis, nephrotic syndrome, glomerulonephritis minimal lesion, nephrolithiasis, nocturia Renal tubular acidosis

Reproductive system and breast disorders Less frequent Frequency unknown Menstrual disorder Female infertility (female fertility decreased), vaginal haemorrhage, breast tenderness

General disorders and administration site conditions Frequent Less frequent Influenza-like illness, peripheral oedema/fluid retention Face oedema, chest pain

Injury, poisoning and procedural complications Frequent Accidental injury

Description of selected adverse reactions: In final data (adjudicated) from the APC and PreSAP trials in patients treated with celecoxib 400 mg daily for up to 3 years (pooled data from both trials), the excess rate over placebo for myocardial infarction was 7.6 events per 1 000 patients (less frequent) and there was no excess rate for stroke (types not differentiated) over placebo.

Drug reaction with Eosinophilia and Systemic Symptoms (DRESS) (see section 4.4)

Reporting of suspected adverse reactions: Reporting of suspected adverse reactions after authorisation of the medicine is important. It allows continued monitoring of the benefit/risk balance of the medicine. Healthcare providers are asked to report any suspected adverse reactions to SAHPRA via the u201c6.04 Adverse Drug Reactions Reporting Formu201d, found online under SAHPRAu2019s publications: https://www.sahpra.org.za/Publications/Index/8.

There is no clinical experience of overdose. Single doses up to 1 200 mg and multiple doses up to 1 200 mg twice daily have been administered to healthy subjects without clinically significant adverse effects. In the event of suspected overdose, appropriate supportive medical care should be provided. Dialysis is unlikely to be an efficient method of medicine removal.